No abstract

FGF21 plays a central role in energy, lipid, and glucose homeostasis. To characterize the pharmacologic effects of FGF21, we administered a long-acting FGF21 analog, PF-05231023, to obese cynomolgus monkeys. PF-05231023 caused a marked decrease in food intake that led to reduced body weight. To assess the effects of PF-05231023 in humans, we conducted a placebo-controlled, multiple ascending-dose study in overweight/obese subjects with type 2 diabetes. PF-05231023 treatment resulted in a significant decrease in body weight, improved plasma lipoprotein profile, and increased adiponectin levels. Importantly, there were no significant effects of PF-05231023 on glycemic control. PF-05231023 treatment led to dose-dependent changes in multiple markers of bone formation and resorption and elevated insulin-like growth factor 1. The favorable effects of PF-05231023 on body weight support further evaluation of this molecule for the treatment of obesity. Longer studies are needed to assess potential direct effects of FGF21 on bone in humans.

Fibroblast growth factor-21 (FGF-21) is a recently discovered metabolic regulator. Here, we investigated the effects of FGF-21 in the pancreatic ␤-cell. In rat islets and INS-1E cells, FGF-21 activated extracellular signal-regulated kinase 1/2 and Akt signaling pathways. In islets isolated from healthy rats, FGF-21 increased insulin mRNA and protein levels but did not potentiate glucose-induced insulin secretion. Islets and INS-1E cells treated with FGF-21 were partially protected from glucolipotoxicity and cytokineinduced apoptosis. In islets isolated from diabetic rodents, FGF-21 treatment increased islet insulin content and glucose-induced insulin secretion. Short-term treatment of normal or db/db mice with FGF-21 lowered plasma levels of insulin and improved glucose clearance compared with vehicle after oral glucose tolerance testing. Constant infusion of FGF-21 for 8 weeks in db/db mice nearly normalized fed blood glucose levels and increased plasma insulin levels. Immunohistochemistry of pancreata from db/db mice showed a substantial increase in the intensity of insulin staining in islets from FGF-21-treated animals as well as a higher number of islets per pancreas section and of insulin-positive cells per islet compared with control. No effect of FGF-21 was observed on islet cell proliferation. In conclusion, preservation of ␤-cell function and survival by FGF-21 may contribute to the beneficial effects of this protein on glucose homeostasis observed in diabetic animals. Diabetes 55:2470 -2478, 2006 P ancreatic ␤-cell dysfunction is a central component of the pathogenesis of all forms of diabetes. Type 1 diabetes manifests from the autoimmune destruction of ␤-cells, whereas type 2 diabetes is characterized by reduced ␤-cell mass and marked functional defects, including impaired first-phase insulin secretion, increased proinsulin-to-insulin ratio, and elevated rate of ␤-cell apoptosis (1-3). The glucose-sensing and insulin-signaling pathways have been shown to play important roles in insulin secretion as well as ␤-cell growth and survival. For example, mice lacking insulin receptors, insulin receptor substrate-2, or Akt (protein kinase B) display marked defects in glucose sensing, insulin secretion, and ␤-cell mass (4 -6). The amount of secreted insulin is determined by the secretory activity of the ␤-cell and the total number of ␤-cells in the pancreas. Glucose plays an essential role in the control of secretory activity of ␤-cells. Metabolism of glucose leads to an increase in the ATP-to-ADP ratio, membrane depolarization, Ca 2ϩ influx, and stimulation of insulin secretion (7). ␤-Cell mass is governed by the balance between ␤-cell growth and ␤-cell death (apoptosis). Type 2 diabetic patients display a progressive loss of ␤-cells caused by an increased rate of ␤-cell apoptosis (8). However, the cause and mechanism(s) responsible for the increased apoptosis rate in type 2 diabetes are not well understood (9). Preventing ␤-cell death and increasing survival of the ␤-cell can be a valuable therapeutic approa...

SUMMARY In obesity, macrophages and other immune cells accumulate in insulin target tissues, promoting a chronic inflammatory state and insulin resistance. Galectin-3 (Gal3), a lectin mainly secreted by macrophages, is elevated in both obese subjects and mice. Administration of Gal3 to mice causes insulin resistance and glucose intolerance, whereas inhibition of Gal3, through either genetic or pharmacologic loss of function, improved insulin sensitivity in obese mice. In vitro treatment with Gal3 directly enhanced macrophage chemotaxis, reduced insulin stimulated glucose uptake in myocytes and 3T3-L1 adipocytes and impaired insulin-mediated suppression of glucose output in primary mouse hepatocytes. Importantly, we found that Gal3 can bind directly to the insulin receptor (IR) and inhibit downstream IR signaling. These observations elucidate a novel role for Gal3 in hepatocytes, adipocytes and myocyte insulin resistance, suggesting that Gal3 can link inflammation to decreased insulin sensitivity. Inhibition of Gal3 could be a new approach to treat insulin resistance.

Background Glucagon-like peptide-1 (GLP-1) receptor agonists are novel agents for type 2 diabetes treatment, offering glucose-dependent insulinotropic effects, reduced glucagonemia and a neutral bodyweight or weight-reducing profile. However, a short half-life (minutes), secondary to rapid inactivation by dipeptidyl peptidase-IV (DPP-IV) and excretion, limits the therapeutic potential of the native GLP-1 hormone. Recently, the GLP-1 receptor agonist exenatide injected subcutaneously twice daily established a novel therapy class. Developing long-acting and efficacious GLP-1 analogues represents a pivotal research goal. We developed a GLP-1 immunoglobulin G (IgG4) Fc fusion protein (LY2189265) with extended pharmacokinetics and activity.